In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features

Tusa, Ignazia; Cheloni, Giulia; Poteti, Martina; Silvano, Angela; Tubita, Alessandro; Lombardi, Zoe; Gozzini, Antonella; Caporale, Roberto; Scappini, Barbara; Sbarba, Persio Dello; Rovida, Elisabetta

doi:10.1007/s11523-020-00741-x

Cited by 5 publications

(6 citation statements)

References 80 publications

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“…In terms of resistance, ponatinib is the most potent TKI used in CML. Furthermore, it appears to target leukaemia stem cells more effectively than imatinib 27 . However, the drug is not used as first line therapy due to a risk for cardiovascular toxicity.…”

Section: Discussionmentioning

confidence: 99%

Rotating between ponatinib and imatinib temporarily increases the efficacy of imatinib as shown in a chronic myeloid leukaemia model

Lindström

Friedman

2022

Sci Rep

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Targeted therapies for chronic myeloid leukaemia (CML) are effective, but rarely curative. Patients typically require treatment indefinitely, which gives ample time for drug resistance to evolve. Drug resistance issues are one of the main causes of death owing to CML, thus any means of preventing resistance are of importance. Drug rotations, wherein treatment is switched periodically between different drugs are one such option, and have been theorized to delay the onset of resistance. In vitro testing of drug rotation therapy is a first step towards applying it in animal or human trials. We developed a method for testing drug rotation protocols in CML cell lines based around culturing cells with a moderate amount of inhibitors interspersed with washing procedures and drug swaps. Drug rotations of imatinib and ponatinib were evaluated in a CML specific cell line, KCL-22. The growth of KCL-22 cells was initially reduced by a drug rotation, but the cells eventually adapted to the protocol. Our results show that ponatinib in a drug rotation temporarily sensitizes the cells to imatinib, but the effect is short-lived and is eventually lost after a few treatment cycles. Possible explanations for this observation are discussed.

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Section: Discussionmentioning

confidence: 99%

Rotating between ponatinib and imatinib temporarily increases the efficacy of imatinib as shown in a chronic myeloid leukaemia model

Lindström

Friedman

2022

Sci Rep

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“…In CML patients, in vitro studies indicate BCR-ABL tyrosine kinase inhibitors (TKIs) to have no efficacy over LSCs and leukemic progenitor cells (LPCs) and, while imatinib initial response rates are overwhelmingly positive, disease recurrence is usually the standard for patients after therapy discontinuation due to remaining Philadelphia-positive (Ph + ) CD34 + cells (101,102). The use of next-generation TKIs, however, seem to be more effective in reducing stem and progenitor cells in CML than imatinib and may point towards a choice for more intensive treatment options in accordance with increased LSCs and LPCs burden (103).…”

Section: Insights Into Clinical Investigationsmentioning

confidence: 99%

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

Barreto

Pessoa²,

Machado³

et al. 2022

Front. Oncol.

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Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.

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“…Moreover, FC enables the determination of the cell line's molecular subtype by analysing overexpression of receptors, such as HER2 or HER3 in breast cancer (Nushtaeva et al, 2019). FC serves as a straightforward tool for quick evaluation of stemness markers like aldehyde-dehydrogenase (ALDH) (Tusa et al, 2020). Moreover, FC is useful not only for immunophenotyping, it has an application assessment of cell apoptosis, viability, and cell cycle, for example in gastric cancer (Zhao et al, 2018).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…The application of cancer cell lines enabled a better understanding of tumour biology and improved drug development (Mitra et al, 2013). The examples of drugs formulated with the use of immortalised cell lines are trastuzumab tested on breast cancer cultures (Zazo et al, 2016), imatinib tested on myelogenous leukaemia cell line (Tusa et al, 2020) or bevacizumab used for therapy of glioblastoma (Simon et al, 2014) and non-small cell lung cancer (Lauro et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

From Donor to the Lab: A Fascinating Journey of Primary Cell Lines

Richter

Piwocka

Musielak

et al. 2021

Front. Cell Dev. Biol.

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Primary cancer cell lines are ex vivo cell cultures originating from resected tissues during biopsies and surgeries. Primary cell cultures are objects of intense research due to their high impact on molecular biology and oncology advancement. Initially, the patient-derived specimen must be subjected to dissociation and isolation. Techniques for tumour dissociation are usually reliant on the organisation of connecting tissue. The most common methods include enzymatic digestion (with collagenase, dispase, and DNase), chemical treatment (with ethylene diamine tetraacetic acid and ethylene glycol tetraacetic acid), or mechanical disaggregation to obtain a uniform cell population. Cells isolated from the tissue specimen are cultured as a monolayer or three-dimensional culture, in the form of multicellular spheroids, scaffold-based cultures (i.e., organoids), or matrix-embedded cultures. Every primary cell line must be characterised to identify its origin, purity, and significant features. The process of characterisation should include different assays utilising specific (extra- and intracellular) markers. The most frequently used approaches comprise immunohistochemistry, immunocytochemistry, western blot, flow cytometry, real-time polymerase chain reaction, karyotyping, confocal microscopy, and next-generation sequencing. The growing body of evidence indicates the validity of the usage of primary cancer cell lines in the formulation of novel anti-cancer treatments and their contribution to drug development.

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In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features

Cited by 5 publications

References 80 publications

Rotating between ponatinib and imatinib temporarily increases the efficacy of imatinib as shown in a chronic myeloid leukaemia model

Rotating between ponatinib and imatinib temporarily increases the efficacy of imatinib as shown in a chronic myeloid leukaemia model

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

From Donor to the Lab: A Fascinating Journey of Primary Cell Lines

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